Petersenrhodes2640

Overexpression of miR-223 significantly increased apoptosis of Caco-2 and FHs74 cells, while proliferation of FHs74 was inhibited. These results suggest that upon binding with NFIA, miR-223 regulates functional effectors in pathways of apoptosis, cell proliferation, G protein signaling, inflammation, and smooth muscle contraction. The miR-223/NFIA axis may play an important role in the pathophysiology of NEC by enhancing inflammation and tissue damage.The CYP2D6 enzyme exhibits large interindividual differences in metabolic activity. Patients are commonly assigned a CYP2D6 phenotype based on their CYP2D6 genotype, but there is a lack of consensus on how to translate genotypes into phenotypes, causing inconsistency in genotype-based dose recommendations. The aim of this study was to quantify and compare the impact of different CYP2D6 genotypes and alleles on CYP2D6 metabolism using a large clinical dataset. A population pharmacokinetic (popPK) model of tedatioxetine and its CYP2D6-dependent metabolite was developed based on pharmacokinetic data from 578 subjects. The CYP2D6-mediated metabolism was quantified for each subject based on estimates from the final popPK model and CYP2D6 activity scores were calculated for each allele using multiple linear regression. The activity scores estimated for the decreased function alleles were 0.46 (CYP2D6*9), 0.34 (CYP2D6*10), 0.01 (CYP2D6*17), 0.65 (CYP2D6*29) and 0.21 (CYP2D6*41). The CYP2D6*17 and CYP2D6*41 alleles were thus associated with the lowest CYP2D6 activity, although only the difference to the CYP2D6*9 allele was shown to be statistically significant (P = 0.02 and P = 0.05, respectively). The study provides new in vivo evidence of the enzyme function of different CYP2D6 genotypes and alleles. Our findings suggest that the activity score assigned to the CYP2D6*41 should be revisited, while CYP2D6*17 appears to exhibit substrate-specific behaviour. Further studies are needed to confirm the findings and to improve the understanding of CYP2D6 genotype-phenotype relationships across substrates.

The role of diastolic dysfunction (DD) in prognostic evaluation in heart failure (HF) patients with impaired systolic function remains unclear. We investigated the impact of echocardiography-defined DD on survival in HF patients with mid-range (HFmrEF, EF 41-49%) and reduced ejection fraction (HFrEF, EF<40%).

A total of 2018 consecutive hospitalized HF patients were retrospectively included and divided in two groups based on baseline EF HFmrEF group (n=951, aged 69±13years, 74.2% male) and HFrEF group (n=1067, aged 68±13years, 76.3% male). Clinical data were collected and analysed. All patients completed ≥1year clinical follow-up. The primary endpoint was defined as all-cause death (including heart transplantation) and cardiovascular (CV)-related death. All-cause mortality (30.8% vs. 24.9%, P=0.003) and CV mortality (19.1% vs. 13.5%, P=0.001) were significantly higher in the HFrEF group than the HFmrEF group during follow-up [median 24 (13-36) months]. All-cause mortality increased in proportion to DD severity (mild, moderate, and severe) in either HFmrEF (17.1%, 25.4%, and 37.0%, P<0.001) or HFrEF (18.9%, 30.3%, and 39.2%, P<0.001) patients. The risk of all-cause mortality [hazard ratio (HR)=1.347, P=0.015] and CV mortality (HR=1.508, P=0.007) was significantly higher in HFrEF patients with severe DD compared with non-severe DD after adjustment for identified clinical and echocardiographic covariates. For HFmrEF patients, severe DD was independently associated with increased all-cause mortality (HR=1.358, P=0.046) but not with CV mortality (HR=1.155, P=0.469).

Echocardiography-defined severe DD is independently associated with increased all-cause mortality in patients with HFmrEF and HFrEF.

Echocardiography-defined severe DD is independently associated with increased all-cause mortality in patients with HFmrEF and HFrEF.Pediatric extrapolation is essential for bringing treatments to the pediatric population, especially for indications where the recruitment of pediatric patients into clinical trials is difficult and where fully powered trials are impossible. Often a similar exposure-response relationship between adult and pediatric patients can be assumed, but just matching exposures can be misleading when some prognostic factors for efficacy differ between those two patient populations. We present an example in liver transplantation where different study designs led to different (time-dependent) hazards between populations. Only after accounting for this difference an apparent mismatch between the extrapolation from adults and the pediatric study could be resolved. This article also exemplifies a clear scientific, methodological approach of pediatric extrapolation, including model building in adults, extrapolation to pediatrics, qualification of the extrapolation, and derivation of the actual pediatric efficacy.

For hepatocellular carcinoma (HCC) located in the left lateral lobe, the optimal surgical procedure is still controversial. This study aimed to optimize surgical strategies and to construct a nomogram to predict the postoperative survival of patients with HCC.

Between 1 January 2005 and 30 September 2018, a total of 493 patients were enrolled. Propensity score matching (PSM) was performed between the left lateral lobectomy (LLL) and left hepatectomy (LH) groups (11). The study endpoints were overall survival (OS), recurrence-free survival (RFS), and safety. A nomogram was generated using a multivariate Cox proportional hazards model. The discriminative ability and calibration of the nomogram were evaluated using C-statistics and calibration plots.

After matching, 87 pairs were included. The LH group had better 1-, 3-, and 5-year OS rates than the LLL group (88%, 73%, and 69% vs. 3,4-Dichlorophenyl isothiocyanate mouse 73%, 57%, and 49%, respectively; p=0.017). The 1-, 3-, and 5-year RFS rates of the LH group were similar to those of the LLL group (64%, 49%, and 46% vs. 63%, 51%, and 42%, respectively; p=0.652). There were no significant differences in postoperative complications. Eight factors were integrated into the nomogram and it had good discriminative ability and calibration.

Our data revealed that compared to LLL, LH may result in better OS and have similar postoperative complications for HCC. The nomogram may serve as a practical tool for the individual prognostic evaluation of patients with HCC.

Our data revealed that compared to LLL, LH may result in better OS and have similar postoperative complications for HCC. The nomogram may serve as a practical tool for the individual prognostic evaluation of patients with HCC.